Saturday, August 29, 2009

You used to hear the expression, "The U.S. has the best health care system in the world." You can still hear it, especially among the crowds that are disrupting town hall meetings to denounce "the government" taking over healthcare. But you're hearing it less and less as informed people realize that the data simply are not there to back up any such claim.

So--what about: "America leads the world in discovering and developing innovative medical therapies"?

Light set out to revisit a 2006 paper by Grabowski and Wang, that claimed that over the years, U.S. drug firms had first caught up with and then exceeded the research output of European companies in meaningful innovations. The original paper by Grabowsky and Wang (http://content.healthaffairs.org/cgi/content/full/25/2/452?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&author1=wang&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&firstpage=452&resourcetype=HWCIT)was a huge favorite of the drug industry, for reasons PhRMA makes clear in its rebuttal. The European scene is characterized by government price controls that limit drug company revenues to about 60 percent of what they can get on the U.S. market. Non-Pharma analyists report that at that rate of return, the European drug companies have plenty to invest in research and make a tidy profit besides. But PhRMA wants to claim that this terrible European climate stifles research, compared to the open, Wild West of America where the companies can charge whatever they darn well please. Anything that suggests that the Europeans are actually doing OK, and maybe the U.S. could do better at lower cost if we emulated some of those European policies, is anathema to PhRMA.

So just how did Light get PhRMA demanding his scalp? He followed all the methods in Garbowski and Wang's original paper, except for one thing. He reasoned that if the drug companies spend twice as much for research in one place as in another, they should ideally see twice as much results in the first location. So he corrected the Grabowski and Wang calculations for how much the companies spent in U.S. vs. Europe. Basically he asked not about total research output but research productivity--how much bang for the buck.

Even before he did his correction, Light noticed that Grabowski and Wang did not paint quite the picture that PhRMA likes to claim. Their research output data showed the U.S. coming up and Europe going down, but Europe did not go down by much, and in several output categories, Europe was still ahead of the U.S.

But the results certainly changed when Light added in the correction for total amount spent. In just about every measure of research productivity, comparing the decades 1982-92 with 1993-2003, Europe improved while the U.S. fell off.

Up till now, Light had basically emulated all the methods of Grabowsky and Wang, with the single exception of adding the correction for level of research funding. But he could not do this for the second major claim of the earlier paper, which was that the vast majority of the new drugs discovered in the U.S. are of great therapeutic importance and significantly impact human health.

Light stated, first, that the original paper never defined the specific criteria for deciding what was a "quality" drug, and second, he corresponded extensively with Grabowsky but could get no satisfactory answer. So instead, Light simply recapitulated the findings of numerous other surveys, some of which were also mentioned in HOOKED. These other surveys all concluded that on average, perhaps one out of nine new drugs discovered during the period 1983-2003 really constitutes a major therapeutic advance. This was the conclusion the FDA was coming to, when it used to rank new drugs--until PhRMA used its lobbying muscle to force the FDA to drop those rankings, as the results were so embarrassing for the industry.

That's what Light had to say--what about the PhRMA rebuttal?

First they accuse Light of using incorrect methods--for instance, deciding which country discovered a new drug by looking at the country where the drug firm has its headquarters. Light's answer here is obvious--you liked the results of Grabowsky and Wang's article; all I am doing is repeating their methods, with one add-on.

Next they dispute the claim that so few new drugs are real advances, but all they have to offer here are anecdotes, no comprehensive data.

Finally they show their true c0lors by saying that it simply has to be true that the U.S. is more productive in pharmaceutical research than Europe, because the U.S. has a market system favorable to drug company profits, it it simply has to be true that research thrives in a favorable market environment. (Don't bother us with facts.) Because if it wasn't true, then there would be no logical reason why the U.S. should not follow Europe's lead in implementing policies that restricted the huge profits the industry can now make in the U.S. So we simply can never be allowed to go down that path.

Thursday, August 27, 2009

In the previous post based on Steve Silberman's excellent Wired article (http://www.wired.com/medtech/drugs/magazine/17-09/ff_placebo_effect?currentPage=all) I took the perspective more favorable to the plight of the drug industry, worried that even good new drugs will fail to pass muster because of an overly inflated placebo response in double-blind trials. Now let's balance out the ledger by looking at the case for the drugs being weak, and that beating up on the placebo as the culprit is simply shooting the messenger.

First of all let's recall the complaints about the industry from critics such as Marcia Angell (The Truth About the Drug Companies). Angell and others argue that the companies get away with a lot, and are allowed to peddle a ton of me-too drugs, because a placebo-controlled trial sets such a low bar. All they have to do is prove their drugs are better than sugar pills. Ideally, for medical practice to move forward, companies would have to show that their new drugs beat out not the placebo, but the standard treatment already on the market (head to head trials)--the sort of comparative effectiveness research the drug industry and its minions are doing their level best to scuttle. So on that basis it seems weird to hear the drug companies complaining that demanding that they prove that their new drugs are better than placebos sets the bar too high, due to claims that the ol' sugar pill is suddenly on steroids.

There are several other passages in Silberman's article that suggest that the real problems may not be what the drug company wishes to think. An example:

"Big Pharma faces additional problems in beating placebo when it comes to psychiatric drugs. One is to accurately define the nature of mental illness. The litmus test of drug efficacy in antidepressant trials is a questionnaire called the Hamilton Depression Rating Scale. The HAM-D was created nearly 50 years ago based on a study of major depressive disorder in patients confined to asylums. Few trial volunteers now suffer from that level of illness. In fact, many experts are starting to wonder if what drug companies now call depression is even the same disease that the HAM-D was designed to diagnose."

Here's a different way to view the same evidence. Most psychiatrists were very impressed with the first generation of drugs (tranquillizers, antidepressants) that appeared in the 1950s. These drugs clinically appeared to make a huge, indeed unprecedented difference in the condition of seriously ill patients, many of whom in those days were hospitalized for their serious mental disorders. The next generation of meds (SSRI antidepressants of the Prozac family; atypical antipsychotics such as Risperdal) simply did not seem to have anywhere near as much oomph as their older counterparts. Had they been tried against patients with the same severity of illness as the older drugs had been used to treat in the 50s, they would probably have flopped. But two things had happened in the meanwhile. First, we stopped throwing the mentally ill into hospitals and now treated a lot of disorders as outpatients. (That was both good and bad and too long a story to tell here.) Even more important, the drug companies realized that so long as they sold antidepressants only for people as seriously depressed as the ones treated in the 1950s--the ones, incidentally, the HAM-D was designed to diagnose--they would be stuck with low sales volumes. So they had to find ways to convince physicians, especially primary care physicians, that somebody who felt down for a few weeks really had depression and really needed to be treated with medications. Only then would sales reach their full potential. So no wonder HAM-D doesn't seem any longer to demarcate the population of "depressed" patients--we have decided that the entire northern hemisphere is depressed and needs meds. And since most of the northern hemisphere has such a mild case of depression that it would get better if you gave out sugar pills, it's not at all surprising that the newer antidepressants don't work any better than sugar pills. In short, don't blame a revved-up placebo effect for the industry's bald-faced marketing ploy of disease mongering.

Another example: "As a psychiatrist, [Merck VP Dr. William] Potter knew that some patients really do seem to get healthier for reasons that have more to do with a doctor's empathy than with the contents of a pill. But it baffled him that drugs he'd been prescribing for years seemed to be struggling to prove their effectiveness." Memo to Dr. Potter: Been there, done that. Think of the physicians who began practice in the 1920s and lived into the 1950s. When the era of the double-blind randomized trial came along after WWII, hardly any of the drugs that were routinely prescribed back in the 1920s were able to pass muster as being superior to placebo. That did not stop the docs of the 20s from prescribing them by the bushel, or from believing in their heart of hearts that the drugs worked just great. Or take more recent double-blind controlled trials of surgical interventions like knee arthroscopy for arthritis and injection of cement for vertebral compression fractures--surgeons and patients alike swear these are extremely valuable procedures, but when you compare them to the sham procedure, they don't work any better.

In summary, one take on the apparent increase in the power of the placebo is that this is a real problem and needs to be addressed lest potentially useful new drugs be discarded. And as it's been historically so difficult to get funding to study the placebo effect in any systematic way, people like me are not likely to complain if the NIH and the drug industry are actually teaming up to pay for this new research into the scope and mechanisms of the placebo effect. (As galling as it may be to read that my own heroes of placebo research, such as Ted Kaptchuk of Harvard and Fabrizio Benedetti of Turin, are now on the drug companies' payrolls.) But another take that seems to be just as plausible is that we have simply run out of really effective and safe new drugs, and the industry stupidly bought into an industrial, assembly-line model of drug discovery and imagined they could keep blockbuster drugs rolling out of their "pipeline" into eternity. They forgot that the reason the post-WWII era was a time of huge advances in pharmacotherapy was because of an older research model that was ascendent between 1900 and 1950, and that made huge breakthroughs in our basic understanding of the mechanisms of disease--without which breakthroughs the blockbuster drugs would never have happened. Today, lacking any comparable commitment to the basic research that unlocks really novel understandings of disease, we should hardly be surprised that the drugs dribbling off the pipeline are mostly me-too drugs. The industry thought it could do its research on the cheap, discovering new drug molecules by an assembly-line process, while at the same time vastly expanding its market by calling a whole lot of people who used to be normal "diseased." That's the business model that was followed for the past couple of decades and its chickens are now coming home to roost.

Meanwhile, how likely are we to learn a lot about the underlying mechanisms of the placebo response--a hugely important question in medical practice? It's hugely important because of a line of research by Benedetti and colleagues in Turin, that Silberman alludes to only briefly at the end of his article. The Turin group has recently focused a lot of attention on studying the placebo effect via a new method--open vs. hidden administration of drugs. Example: patients after surgery keep regular pain-level diaries. All get IV injections of narcotic painkillers at intervals. Half of them get "open" injections--a doctor or nurse walks in, says "here's your pain shot" and visibly injects something into the IV tubing. Half get a "hidden" administration-- a computer-timed pump behind a screen injects the medication into the IV line without the patient's knowledge.

In virtually all the trials done in this manner so far, the results are that the open administration of the drug produces about twice as great an effect as the hidden adminstration. Maybe you had better be sitting down when you seriously ponder that concept--that perhaps half of the power of all the drugs that we currently consume is due to the placebo effect, our positive expectations of relief based on knowing that we are getting the drug, and not on the purely chemical properties of the drug. Of course we don't know that this is true for all drugs because only a few have been subjected to the open vs. hidden method. But hopefully you can now see why I say that it is huge that we better understand what is going on here.

So I ask whether the right way to find out what is going on in this hugely important area of medicine is what Silberman characterized as follows (repeated from previous post): "Under the auspices of the NIH, Potter and his colleagues are acquiring decades of trial data—including blood and DNA samples—to determine which variables are responsible for the apparent rise in the placebo effect. Merck, Lilly, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi-Aventis, Johnson & Johnson, and other major firms are funding the study, and the process of scrubbing volunteers' names and other personal information from the database is about to begin.In typically secretive industry fashion, the existence of the project itself is being kept under wraps. NIH staffers are willing to talk about it only anonymously, concerned about offending the companies paying for it."

If there's this much secrecy involved, how can we be sure that the object of the research is really to understand better how the placebo response works--as opposed to simply figuring out better ways to cook the books when you do a clinical trial to make the drug appear to be better than placebo, no matter how good the placebo turns out to be? (Such as present-day trials designed with placebo run-in periods aimed at eliminating from the study all subjects who seem to be excellent placebo responders?)

If you say, but of course we can trust the drug companies to do what's scientifically correct, I remind you of another passage in Silberman's article: "Thinking that something crucial may have been overlooked, Potter tapped an IT geek named David DeBrota to help him comb through the Lilly database of published and unpublished trials—including those that the company had kept secret because of high placebo response." Omigosh! A big drug company suppressing data because the results didn't come out the way the marketers wanted? What a shock to all readers of this blog...

It's right a good deal of the time, and where it's wrong, it's wrong in a fascinating way. I expect to get several posts out of Silberman's article, to keep each within manageable length.

The subject of this post is a "pro-industry" assessment of Silberman's main claim--that somehow, in recent years, the placebo effect in drug research has gotten more powerful, making it harder for the companies to prove that even good drugs are truly superior to placebo (the minimum bar for FDA approval in most cases). The next post will be the skeptical assessment of the same claim.

The news flash that Silberman passes on--citing the work of psychiatrist and Merck VP William Potter--was actually something we had a pretty good glimmer of a quarter-century ago, from a classic placebo paper by anthropologist Dan Moerman. Moerman did a meta-analysis (actually one of the very first I think) of 31 studies of cimetidine vs. placebo. (Anyone remember Tagamet? Before the "purple pill" era of Prilosec and its lookalikes, cimetidine was the real breakthrough drug, turning peptic ulcers from a surgical into a medically treatable condition.) Moerman showed that on average, the rate of good therapeutic responses among those given placebos for their ulcer disease, in the context of these double-blind studies (with ulcer size being measured by endoscope visualization, so we are talking here about "objective" responses, not merely "subjective" relief of symptoms) was about one-third. That was sort of reassuring as it matched the estimate given by Henry Beecher in his previously classic, but now widely debunked paper, "The Powerful Placebo" published in 1955.

Moerman proceeded to show that the one-third figure was more obscuring than enlightening, because the main phenomenon about placebo response rates were their wide variability. The placebo response in one study hit a low of 10 percent, and in another study topped out at 80 percent. If you looked at all 31 studies, about half showed cimetidine being superior to placebo, and half not. The cimetidine response rate was actually very uniform--about 75 percent of subjects improved in the drug group in nearly every study. So whether cimetidine was superior to placebo or not said nothing about how cimetidine performed; it was all about how well placebo performed.

(Sidebar to the main story line: The astute reader will already be jumping up and down, that I have confused two quite different phenomena--the true placebo response rate, which is the healing that occurs because you take a placebo; and the natural history of peptic ulcer disease, which says that if you wait long enough, most ulcers will heal on their own, even if you took nothing at all. The placebo group in a typical double-blind controlled trial is subject to both effects, and the trial methodology does not distinguish which is which. But this was one of the significant points about what Moreman found. Can you really argue that peptic ulcers heal by themselves only 10 percent of the time in one place, but 80 percent of the time in another? The wide variability among study sites and contexts strongly suggested that it was most likely the "true placebo effect" that varied from study to study, while the "natural history effect" would be expected to be present, but not to be so widely variable.)

You see right away the implications for the drug company. Imagine that through bad karma, all 15-16 or however many studies that happened to show cimetidine not being any better than placebo, had been the first set of studies performed. The companies would never have taken the drug to the FDA for approval. And both in those studies and also based on extensive clinical and research experience subsequently, cimetidine is as near as you are going to get to a really good drug. Indeed, we now think that among all the patients being prescribed expensive proton-pump-inhibitor drugs like Nexium, the majority would probably have gotten just as much better, at far lower cost, on drugs of the cimetidine class.

Silberman's article takes this story up to date by discussing recent research, especially in psychiatric conditions like depression, that seem to indicate that there has been a steady upward placebo creep in recent years, so that it is getting harder and harder to show that even supposedly good new antidepressants are better than placebo. Why this might be happening is the mystery the article delves into. Potter years ago suggested that the problem was so big that it would behoove the drug companies actually to join forces and review their pooled data sets to try to crack the puzzle and figure out how better to test their drugs so that they stood a fighting chance against placebo. For years the companies said, no way will we share our data with our competition. Finally they have seen the wisdom in Potter's idea and NIH has gotten involved as well. Here's Silberman's summary:

"Under the auspices of the NIH, Potter and his colleagues are acquiring decades of trial data—including blood and DNA samples—to determine which variables are responsible for the apparent rise in the placebo effect. Merck, Lilly, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi-Aventis, Johnson & Johnson, and other major firms are funding the study, and the process of scrubbing volunteers' names and other personal information from the database is about to begin.In typically secretive industry fashion, the existence of the project itself is being kept under wraps. NIH staffers are willing to talk about it only anonymously, concerned about offending the companies paying for it."

(Now, anything this secretive has its own set of problems which we will have to address in a later post.)

Silberman tosses around a few preliminary hypotheses about why placebos supposedly work so much better these days than before, of which the most interesting and ironic one is that the companies have poisoned their own well with their massive DTC advertising campaigns. Data suggest that placebo response is commonly much higher in developed countries than when the same studies are done in poorer nations. And of course the concentration of prescription drug advertising, brainwashing the viewer into thinking that a pill conquers every ill, is much greater in the former nations. In a picturesque phrase, Silberman summarizes, "one way that placebo aids recovery is by hacking the mind's ability to predict the future." Heavy doses of drug advertising means that the brain predicts the future in a way that maximizes reaction to placebos.

That's one way to spin all this. Next I'll look at it from a more skeptical direction.

The blog posting contains interesting allegations regarding one Roger (or Rogerio) Lobo, at one time chair of Obstetrics and Gynecology at Columbia University med school. (I've not sought any documentation of these old charges beyond what's on the blog, hence the "allegations.") Seems the good Dr. Lobo was caught up on a scam some years back, when an article appeared with him listed as first author claiming that intercessory prayer had greatly increased the rate of success in an infertility clinic. Eventually the research "methods" were completely debunked and one of the "investigators" was actually indicted for fraud. Columbia circled the wagons and defended Dr. Lobo, since as he noted he had not really had anything to do with the research itself--he agreed to have his name put on the paper only after all the "research" was completed and without seeing any of the raw data. Remember, this was what was said in his defense. Supposedly all this blew over and the journal did not even see fit to formally retract the paper--but by coincidence, Dr. Lobo was no longer chair of his department.

Now, says the blog, guess who is listed as one of the Wyeth ghost authors willing (for a fee) to put their names on ghost-written papers praising Wyeth's Prempro. Yup, none other than good ol' Dr. Lobo.

This is all very interesting but what most caught my eye were some of the comments posted to the blog in response to this:

"Must say, I remain baffled as to why medical schools are so scandalously different from other parts of the American university – so indifferent to the origins and legitimacy of their faculty’s work, and to their conflicts of interest... I’ve only begun to understand that there’s a kind of systemic, overlooked fraudulence about many medical faculties. The sort of thing that spawns Michael Jackson’s drugmeister, Arnold Klein — still on UCLA’s faculty far as I can tell…""More than a quarter century ago, when Nicholas Wade and William Broad published their disturbing book, Betrayers of the Truth, describing some of the most egregious and notorious cases of deceit and fraud in science, a very disturbing pattern emerged: Medical schools were spawning a disproportionate number of crooks, liars, and cheats. Despite the famous oath physicians take to do no harm, a shocking majority of frauds in science were MDs, rather than Ph.Ds. ...I haven’t seen a more recent comparison. But, considering how many medical schools have lowered some of their ethical standards, I suspect the discrepancy has grown much worse. I’ve often watched with dismay as medical school academics lie and misrepresent their research data repeatedly with impunity. I’ve seen much less of that in non-medical fields of research.""[About] a PhD grad student who wantonly created his data used in several published research papers, I thought: O.K. Clearly not all of the science frauds are MDs.But then I read deeper into the article and saw that this fraud had earned his MD six years ago. He then went back to get his PhD — apparently in creative fiction.Louisiana State University won’t comment whether the fraud will lose the PhD earned last year with the help of that bogus data. However, a spokesman said he’s not going to be stripped of his MD. I’m not surprised. It’s becoming clearer and clearer that medical schools have much lower ethical standards than the other sciences.Nobody who jeopardizes the health and lives of patients by publishing fraudulent clinical data should be allowed to practice medicine. That should be clear. But it’s not, at least to those who train, license, and discipline physicians in America." PS--on the LSU student and his misdeeds see: http://www.the-scientist.com/blog/display/55917/

So this is a handy reminder as to why us "pharmascolds" are in this game to start with. You guys over at ACRE, now do you get it? Here is what we are up against. There are reports of scandals among academic physicians, and what is the reaction of our fellow academics in other disciplines? "Oh my heavens, what a shock, to find physicians acting in this manner"? Not at all. The reaction is-- "Ho hum. So what did you expect anyway? After all, these bozos work in the medical school."

A little bit of history: In the middle of the 19th century, many U.S. universities, starting with Harvard and going on down the list, had medical schools officially affiliated with them. But it was widely understood that the med school was a completely different breed of animal from the "real" university. The med school was a proprietary operation that existed to make money. Students were admitted with no college degree and sometimes without even a high school diploma, they bought tickets to attend lectures, and if they sat through the right number of lectures, they got their MD degree. The "professors" of the medical school were basically practitioners from town who wanted to pad their incomes by selling those lecture tickets, the proceeds from which they got to pocket, and whose academic credentials would never have gotten them in the door of the university proper.

Then, starting with schools like Harvard and Penn in the 1880s and culminating with Johns Hopkins in the 1890s and finally the Flexner Report of 1910, medical education reformed itself. The moneychangers were thrown out of the temple of academe; being a med school professor was newly seen as a full time job--indeed, a relatively low-paying one--and not as a cushy way of moonlighting for cash; and standards of medical education rose to the level that gained universal respect by the middle 20th c.

So are we now witnessing the return of proprietary medicine--the med school newly emerging as a blight on the university scene because of its low ethical standards and unabashed pursuit of cash? The one thing doubtful about this picture, sadly, is whether the rest of the university can give itself any ethical airs, or whether the selling-out of educational values and ethical integrity is pretty much across the board.

Let's see what's going on here by first considering a town-gown problem--how unfair the standard practice of pharmaceutical ghostwriting is to practicing docs and the drug reps who sell to them, compared to their academic counterparts:

Academic physicians get to pad their vitae by the easy route of getting medical communication companies to write their journal articles for them, at drug company expense--because they have a name (or more often, the prestigious name of their medical school) the company wants to see in the credits of a journal article. The practitioner grunt out in the boonies? Who cares what he thinks about a drug?

The academic doc gets to put a minimum of a thousand bucks in his/her pocket (many say it's more but I'm still waiting for something in writing to back that up), all for the simple act of sticking a name on an article somebody else wrote. Where's the practicing guy going to lay hands on that kind of bread for trashing his own integrity?

Think of all the editorial assistance an academic gets from the communications company--the best editorial help, a thorough literature search free of charge, the nicest figures and tables, and most important, a well-researched strategy to match the article with exactly that journal whose editor is known to be dumb or negligent enough to print it. The practitioner, not being in a big medical center, needs that help even more--but gets none of it.

Finally think of it from the drug rep's point of view. The academic doc gets to pad his reputation and puts cash in his pocket too, and therefore feels even more beholden to the kindly drug firm that made it all possible. The drug rep is desperate for something she can give her prize prescribers, to keep them loyal and eager for future detail visits. But can she pass around the same goodies that the academic docs routinely get? NOOOOO.

Well, you drug reps and practicing docs out there in Haystack Junction, help is on the way--or at least it was in 2000, when SmithKline Beecham (now GlaxoSmithKline) introduced a new rep assistance program to boost sales of its antidepressant, Paxil. Somebody at headquarters must have had a real hoot when they were permitted to name the new program CASPPER (for CAse Study Publications for PEer Review). I'd personally be curious as to how many average drug reps got the joke; and of course, the practitioners to be reeled in by the reps presumably never learned what the program was called.

A sidebar-- we now know about CASPPER, says Matthew Perrone of AP, because the law firm representing hundreds of former Paxil users in a class action suit against GSK uncovered the document in its discovery process, and the judge approved its release. (More proof of the unfortunate adage that if drug companies were not regularly sued, we'd have no idea what the heck was really going on.)

CASPPER, according to its 14-page brochure, was cleverly designed to meet two needs simultaneously. Drug reps needed goodies to pass out to their best prescribers, or big-volume prescribers they thought could be turned into better ones. And the company needed more positive buzz about Paxil in the journals, especially of a sort that reflected the use of the drug in actual practice, even if the resulting papers appeared in smaller journals and were less impressive than major academic studies.

The drug rep was instructed to wait for docs, during detail visits, to mention experiences they'd had with Paxil that demonstrated significant success, or that countered claims by Paxil's competitors about side effects or other problems. (Hmm. Side effects. Could that possibly be why those hundreds of folks are now suing GSK?) The rep would then ask the doc if she ever thought of writing that experience up as a case report for a journal.

The doc would be expected to say--are you crazy, I'm a busy practitioner, look at how full my waiting room is (they are all waiting longer because I'm wasting my time talking with drug reps instead of seeing patients). How would I have the time to write an article, send it to a journal, and so on?

At this point the drug rep pulls the CASPPER rabbit out of his hat and tells the doc all the services that the drug company has contracted for, from a firm called Complete Healthcare Communications (CHC)--to the tune of a budget for 50 articles to be prepared in the year 2000 (the only year mentioned in the brochure). Once the doc suggests a topic and presumably describes his succesful case, CHC takes it from there--developing the topic, doing a thorough literature review, assembling sophisticated figures and tables, preparing the detailed first draft, noting all points at which the "author" must add information, revising based on "author's" responses, and finally developing the complete strategy for submission to the journal, even to photocopying the correct number of copies (recall the olden days of 2000 where journals were not yet demanding e-submission?). They only missed one beat that I could see. The office practitioner was given a sample cover letter to submit to the journal, that she was supposed to have retyped on her own office stationery. Obviously that was an oversight. CHC and the drug firm ought simply to have asked for a blank sheet of her stationery and written the cover letter on it themselves. I mean, if you are going to be a full service ghostwiting business, might as well do the thing right.

Ideal result--a case report touting the joys of Paxil appears in a low-level journal, but becomes a reprint that reps can hand out saying, "Here's a case report from a practicing physician just like you, telling us just how well Paxil works." The doc, who has the thrill of seeing her name in lights as a published author, is ever so grateful to the wonderful Paxil rep, and the rep can do no wrong so far as she is concerned from then on. The rep by the way never happens to let on that the academic doc up the street gets paid $1000 for that same service, so the practitioner has no idea that she's missing out on that little perk.

After admiring the sheer brilliance of CASPPER, we are actually rather let down to hear from GSK spokesperson Mary Anne Rhyne, "The program was not heavily used and was discontinued a number of years ago." Still, in its salad days, CASPPER produced articles in five journals between 2000 and 2002, including the American Journal of Psychiatry and the Journal of the American Academy of Child and Adolescent Psychiatry, not exactly chopped liver.

The sermon is part of our ongoing series on the newer generation of antidepressants (primarily those known as SSRIs), and how the industry has routinely suppressed evidence of serious side effects and less-than-ideal efectiveness. The result has been many patients being put on expensive and often not very helpful drugs, that often cause unpleasant side effects and rarely cause life-threatening side effects. Had the truth been known from the get-go, it's likely that far fewer of these patients would have been subjected to this trial-by-pharmacopoeia.

The true story of these drugs has slowly been making itself known--no thanks to the drug industry--through recent systematic reviews of the literature, both published and unpublished. The present meta-analysis comes from an unlikely source--the FDA. The authors explain that after an FDA advisory committee recommended a black box warning on children and adolescents due to emerging evidence of increased risk of suicidal thoughts when taking SSRIs, the agency was ordered to look into the extent to which this same adverse reaction might be found in adults.

Now, here's the big news. Normally when investigators do a meta-analysis they play a grand game of "let's pretend." They find, let's say, 10 studies of a certain drug compared to placebo. And let's say that each study enrolls 100 subjects. The investigators then re-analyze the data as if they were doing a brand new study of the drug vs. placebo with 1000 subjects enrolled. But this "as if" game is flawed by the fact that they do not, as a rule, have direct access to the raw numbers generated in each of the previous 10 studies. They have the published results and have to job backwards from those results to imagine what would have happened if there had been a grand study involving all 100 subjects instead of 10 studies with only 100 each. (That's the simplest version, ignoring the fact that each study might have had slightly different conditions and enrolled a different population of subjects so that you really mix apples and oranges by combining the studies in the first place.)

Now, if you happen to be the FDA, this is not how you have to do a meta-analysis. You can demand that the companies supply you with all their raw data. So you can get much closer to re-investigating the actual data of each study. This is what the FDA investigators did with the antidepressant studies. They were able to sum the data from 372 separate studies of 12 different SSRI-type antidepressants. Were their methods fool-proof? No. If drug company research people managed to completely hide the fact that subject #36 (let's say) had suicidal thoughts on day 8 of taking the drug, by misclassifying the reaction as "increased anxiety" rather than "suicidal thoughts," I don't think these authors could have seen through the scam. But compared to the more usual meta-analysis, this was obviously a much deeper-drilled study.

What did the authors find? Basically, the likelihood of suicidal thoughts and behavior with this group of antidepressants is highly age-related. The increased risk extends beyond adolescence and goes up to about age 25. From age 25 to 64, either the end result is a toss-up, or the drugs are very slightly protective. Above age 65, the drugs seem to work to significantly reduce the risks of suicidal stuff.

One comment in the paper by Stone et al. highlights the problem of practicing physicians, poor blokes, who had to rely on published medical journal articles to figure out when and whether to prescribe these drugs: "Some of the trials included in the analysis were the basis of articles published in peer reviewed journals but the question of suicidality was not considered in any detail by the authors or reviewers." Hmm--the raw data of the study, when sifted through carefully by FDA gumshoes, provided evidence of some significant risks of suicidality; but you'd never get a clue that this was so by reading what was published in a peer-reviewed medical journal. So has the medical scientific literature been effectively captured and held hostage by the pharmaceutical industry? You decide.

So let's step back and take in the big picture. Does this mean that these drugs are the tool of the devil? Hardly-- even in the worst case scenario, only a handful of patients have serious adverse reactions. Does this mean that these extermely useful, even life-saving drugs have been unfairly maligned by their anti-Pharma critics ("pharmascolds")? Not that either. If the best these drugs can show for suicidal behavior in the huge mass of non-elderly patients, age 25-64, is close to a toss-up, then it hardly seems to be the case that these drugs are the greatest thing since sliced bread.

The real take-home message seems to be that we began consuming mass quantities of these drugs (as the old "Coneheads" skit on "Saturday Night Live" would have put it) now nearly two decades ago. The true scientific picture of who should be given these drugs, who should not be given them, and what will happen to each group if they take them, seems to be emerging only in the last couple of years. And it is emerging not at the instigation of, but over the dead body of the pharmaceutical industry research enterprise. This is hardly a vote of confidence for an industry that enjoys portraying its mission as the discovery of new, safer and more effective drugs, and its relationship with the medical profession as "educational."

Saturday, August 22, 2009

In previous posts I referred to documents released as a result of the lawsuits against Wyeth for their hormone replacement therapy, that showed the concerted campaign that company used to place ghostwritten articles praising HRT products in medical journals. Up till now, thanks to a couple opf media sources, we had ready access only to some of the pile of documents. The journal PLoS Medicine has just released the entire stock of documents, said to be about 1500 pages: http://www.plosmedicine.org/static/ghostwriting.action Sadly these are as yet unindexed so anyone trying to sort through them will have to do so manually, though there are plans to create an index.

What’s clear is that ghostwriting can no longer be considered one of the “dirty little secrets” of medical publishing that nothing can be done about. While editors, medical schools, and universities have turned a blind eye to, or at the least failed to tackle head-on the pervasive presence of ghostwriting, drug companies and medical education and communication companies have built a vast and profitable ghostwriting industry. Recruitment of academic “authors” appears, within some academic circles, to have come to be considered acceptable, and marketing campaigns are no longer orchestrated around paid display advertisements but instead center on “evidence” provided by seemingly respectable academic review articles, original research articles, and even reports of clinical trials. What, a cynical reader might ask, can I truly trust as being unbiased? The answer is that, sadly, for some or even many journal articles, we just don’t know.Till now, when the topic of ghostwriting comes up, journal editors mostly wring their hands and pass the buck. Of course it's unethical, egregious, and generally horrible, but what can we do? We can't play private eye and investigate every paper that's submitted to us. We are helpless if the academic institutions at which the "ghost authors" work fail to take strong action and allow these transgressions to continue. Not so fast, says PLoS Medicine:

But journal polices should also include enforceable sanctions. For example, if nothing is declared on submission but inappropriate involvement of a medical writer subsequently comes to light, any papers where this breach is substantiated should be immediately retracted and those authors found to have not declared such interest should be banned from any subsequent publication in the journal and their misconduct reported to their institutions.In the case of the documents deposited here, a good start, and a signal of the seriousness of journals’ intent, would be the formal retraction of all the papers mentioned in which ghostwriting has been conclusively shown. Institutions whose academics are shown to be involved should investigate as a matter of urgency.It's scary, isn't it, to think that even in the past when ghostwriting has been proven, the journal has not even gone so far as to retract the paper formally? (Not that that justifies the inaction of the academic institution who either does nothing or else slaps the hand of the ghost author, who's usually locally revered for having brought all that drug company cash into the med school coffers.)

The editorial ends with some observations that are pondered all too seldom (especially the last sentence):

Whatever the reasons, as the pipeline for new drugs dries up and companies increasingly scramble for an ever-diminishing proportion of the market in “me-too” drugs, the medical publishing and pharmaceutical industries and the medical academic community have become locked into a cycle of mutual dependency, in which truth and a lack of bias have come to be seen as optional extras. Medical journal editors need to decide whether they want to roll over and just join the marketing departments of pharmaceutical companies. Authors who put their names to such papers need to consider whether doing so is more important than having a medical literature that can be believed in. Politicians need to consider the harm done by an environment that incites companies into insane races for profit rather than for medical need. And companies need to consider whether the arms race they have started will in the end benefit anyone. After all, even drug company employees get sick; do they trust ghost authors?(Thanks to Dr. Adriane Fugh-Berman for this tip.)

Wednesday, August 5, 2009

This firm recently sponsored a conference for drug reps and their handlers, Sales Force Effectiveness USA 2009 (see previous posting, http://brodyhooked.blogspot.com/search?q=eyeforpharma). Not having $2295 for the registration fee burning a hole in my pocket at the time, I elected not to register for the conference, so I'm glad that Lisa Roner has posted about a panel discussion among practicing physicians that occurred there.

Ms. Roner tells us that these 5 physicians on the panel had a point of view quite different from what most of us have been reading about lately, and from the pontifications of various medical organizations. These docs are thrilled to spend time visiting with reps. They highly value the information and materials that reps provide for them. They appreciate shortcuts given how busy they are, but getting rid of reps or diminishing Pharma influence over their practice is the last thing on their to-do list.

Roner suggests:

When asked why their attitudes toward reps and their usefulness seemed to differ from so much from what we hear from professional medical associations today, one participant explained that most of the boards that state positions on such matters are populated by academic MDs, whose perspectives and available time for researching new information on prescription drugs is different than that of practicing clinicians. It was interesting to hear that the organizations that claim to speak for physicians perhaps don’t really represent the views of those truly serving patients....In short, although they had some suggestions for improvement, this was not a group that appeared to want to distance itself from pharma or its reps. In fact, it was quite the opposite . These doctors saw value in what pharma and its reps have to offer. Funny that’s not what we hear in the media or from the political lobby. Have we been listening to the wrong “doctors?”

So-- just where did this much more representative group of doctors, who "truly" serve their patients (while academic physicians, apparently, only pretend to) come from? The post does not say exactly how they were chosen, except to say that the panel was moderated by Hank Parish, VP of Doctor Directory. Just what exactly is Doctor Directory? Business Week e-trade tells us:

DoctorDirectory.com, Inc. operates as an online directory for finding a doctor by specialty. Its solutions include IncreaseRx, market research, eSampling, consumer email, physician email, eDetailing, custom directory, and advertising. The company also provides patients from online directory, cash for online research projects, online sample closet, and practice management advice to the physicians. It serves pharmaceutical prescription drug manufacturing companies, patients, and physicians.

I like that last part-- the company serves "pharmaceutical prescription drug manufacturing companies, patients, and physicians"--presumably in that order. So a group of 5 physicians selected by that outfit (presumably) is a more reliable sample of physician sentiment than what is said by major medical organizations?

Now, perhaps it does--perhaps the views of these 5 docs are truly more representative of the rank and file than anything I or the AMA or the AAMC says. That's why it's still important to recall a key fact about ethics--it's not a popularity contest. You don't get to say that something is ethical merely by putting it to a vote. Even if 90 percent of US physicians believe what these dudes said in their panel, it would not make it the ethically correct answer.

It would just make it a sad commentary on the state of American medicine.

I am forced to write to you as a result of the New York Times article today in which a member of your faculty--a department chair in fact--is quoted as taking a position on the ghostwriting of medical journal articles that I hope you'll feel obligated to repudiate:

The Times article states that court-released documents list 26 Wyeth ghostwritten papers that were published in 18 journals. Ideally I would be addressing a letter such as this to the deans of all medical schools involved. However, a search of the web as of midday today did not yield access to the full list of putative authors, and so the name of your faculty member is currently the only one that I know.

Do I enjoy pointing fingers at my colleagues in academic medicine in public? Hardly. Do I have any personal animosity against you or any member of your faculty? Not at all. But I am forced to write this for two reasons, one general and one specific.

The general reason is that, while academic medical leaders and journal editors continue to condemn ghostwriting as an ethically indefensible practice, it remains virtually impossible to discover a single academic physician who has been caught putting his or her name to a ghostwritten article, and then suffered any adverse consequences whatsoever. If this is a crime without any punishment attached, how can the general public possibly take us seriously when we proclaim our ethical stance? So much as we shrink from making examples of some of our colleagues, how else are we to establish that this truly is a serious business and that we mean what we say?

There is a more specific reason in this case. Dr. Gloria A. Bachmann, professor and interim chair of your department of Obstetrics, Gynecology and Reproductive Sciences, was reported by the Times to have affixed her name to a paper written by a PR firm hired by Wyeth, and published in 2005 in the Journal of Reproductive Medicine. Copies of e-mails from 2003, released with other documents by the court overseeing lawsuits against Wyeth for the marketing of their hormone replacement therapy, show that Dr. Bachmnn agreed to affix her name as sole author to the paper after making one correction only to the manuscript.

Dr. Bachman, on being contacted by the Times, might have said many things. She might have apologized for her lapse of good ethical practice. She might have noted how common ghostwriting has been among her circle of academic physicians, and how recent have been vocal objections to the practice--so that the standards of behavior in 2009 might not be the same as in 2003.

Dr. Bachman said none of these things. Instead she staunchly defended her behavior:“There was a need for a review article and I said ‘Yes, I will review the draft and make sure it is accurate,’ ” Dr. Bachmann said in an interview Tuesday. “This is my work, this is what I believe, this is reflective of my view.”So I am now forced to ask you for your position as Dean of the medical school. Do you agree with Dr. Bachmann, that it is perfectly all right for your faculty to attach their names to articles in medical journals that they did not write, so long as the article is accurate and they agree with the views expressed therein? Do you believe that would be the position of the journal editor? Do you intend to advise Dr. Bachmann that her publicly stated position is at odds with the ethical values of your medical school? (I attempted to consult your school's conflict of interest policy to see if there were specific provisions about ghostwriting, but your policy appears to be password protected to exclude non-RWJMS readers.)

Those of us who believe that some degree of public trust in medicine hangs in the balance are concerned to hear your answers.

Monday, August 3, 2009

Alicia Mundy in the Wall Street Journal (http://sbk.online.wsj.com/article/SB124917341780899303.html; subscription required) writes how the House Energy and Commerce Committee voted 47-11 to hand the biotech industry a major victory in an amendment to the health reform bill, handing a setback to the Administration.

The industry gets a full 12 years' patent exclusivity for its expensive biologic products, which Obama and other Democratic leaders had hoped to whittle down to 5-7 years before generic competition would be allowed. Many of the worst "evergreening" abuses, by which the brand name drug maker can extend patent rights by making only minor tweaks in a drug, also get the green light under these amendments.

If this is a sign of how likely Congress is to stand up to the Pharma and biotech lobbies to pass meaningful health reform, it is not encouraging.

Today I can put my feet up and let Dr. Roy Poses' Health Care Renewal blog do all the heavy lifting.

First: Recent relevations about Dr. David Polly, a spine surgeon at U-MN. Seems he made about a cool million serving as a consultant to Medtronic, the device maker that supplies many orthopedic products. Dr. Polly for instance testified before Congress and claimed to be representing the national orthopedic academy, but did not disclose that Medtronic paid all his expenses. The fun part of this post is that you get to look at the actual billing records that Dr. Polly sent to Medtronic, which were released after being requested by Sen. Charles Grassley. In case you wondered what 5 minutes of Dr. Polly's time is worth, it's $49.48; for a whole day it's above $4000. The real issue is that the records show a lot of activity clearly related to marketing and lobbying, and much less clearly related to research and scientific progress.

Next: A judge has ruled against drug maker Wyeth in a big lawsuit about hormone replacement therapy. Documents regarding Wyeth's extensive ghostwriting campaign in relation to the drugs have been ordered to be released. Presumably the records deal with some 40 papers published in medical journals. But don't worry--the Wyeth lawyer has rushed to reassure us that while the papers were indeed ghostwritten and hence fraudulent, they are nonetheless "fair, balanced, and scientific."